Clonal evolution as detected by interphase fluorescence in situ hybridization is associated with worse overall survival in a population-based analysis of patients with chronic lymphocytic leukemia in British Columbia, Canada.

This study evaluates prognostic markers as predictors of clonal evolution (CE) and assesses the impact of CE on overall survival (OS) in a population-based cohort of 159 consecutive eligible patients with chronic lymphocytic leukemia (CLL) obtained from the British Columbia Provincial CLL Database. CE was detected by interphase fluorescence in situ hybridization (FISH) in 34/159 patients (21%) with 65% of CE patients acquiring deletion 17p or 11q. CD38 positive status (≥30%) on flow cytometry predicted 2.7 times increased risk of high-risk CE (acquisition of deletion 17p or 11q) on multivariate analysis. Prior CLL therapy was not a significant predictor of CE. CE was associated with 4.1 times greater risk of death when analyzed as a time-dependent variable for OS after adjusting for age, lymphocyte count, and FISH timing. High-risk CE was associated with worse OS while acquisition of low/intermediate-risk abnormalities (trisomy 12, deletion 13q, and IGH translocation) had no difference in OS. Our study demonstrates the negative impact of CE detected by FISH on OS in this population-based cohort. These data provide support for repeating FISH testing during CLL follow-up as patients with high-risk CE have reduced survival and may require closer observation.

Immunoglobulin heavy chain (IGH@) translocations negatively impact treatment-free survival for chronic lymphocytic leukemia patients who have an isolated deletion 13q abnormality.

Immunoglobulin heavy chain translocations (t(IGH@)) are suggested to portend a poor prognosis in chronic lymphocytic leukemia (CLL). To determine the clinical significance of a t(IGH@) on CLL-specific cytogenetic abnormalities, we analyzed the outcomes of 142 CLL patients referred for fluorescence in situ hybridization (FISH) analysis with our standard FISH panel, which includes testing for a t(IGH@). Whereas patients with unfavorable (deletion 17p, deletion 11q) and intermediate (trisomy 12, normal FISH) cytogenetics with concomitant t(IGH@) had similar median treatment-free survival (TFS) as those without a t(IGH@), patients with deletion 13q (del13q) and a t(IGH@) had significantly worse TFS than those without a t(IGH@): median TFS 4.7 versus 8.0 years, P = 0.03 (hazard ratio 4.21, 95% confidence interval 1.06-16.69 y, P = 0.04 in multivariate analysis after adjusting for age, sex, Rai stage, and white blood cell count). The presence of a t(IGH@) further stratified patients with del13q into two prognostic entities, whereby outcomes of those with coexistent del13q and a t(IGH@) were similar to outcomes of those with high risk cytogenetics. Knowledge of the t(IGH@) status in CLL is therefore of clinical importance, as del13q patients with concomitant t(IGH@) may not retain the previously expected favorable outcome.

Allogeneic haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: outcome in a 20-year cohort.

The curative potential of allogeneic haematopoietic stem cell transplant (allo HSCT) in chronic lymphocytic leukaemia CLL is established, with a demonstrated role for graft-versus-leukaemia and less certainty for other factors in determining outcome. The first two decades of CLL patients proceeding to allo HSCT at the Leukaemia/Bone Marrow Transplant Program of British Columbia (n = 49 consecutive, 1991-2009) were studied to clarify factors predicting outcome. The donor was related in 29 (59%) and unrelated in 20 (41%). Conditioning was reduced-intensity in 27 (55%) and myeloablative in 22 (45%). Thirty-one of 49 patients survive with median follow-up of 5 years (0·2-15). Cumulative incidence of non-relapse mortality; complete remission (CR); clearance of fluorescence in situ hybridization (FISH) abnormality and progression at 10 years was 36%; 69%; 55% and 22%. Overall survival (OS) was 63% at 2 years; 55% at 5 years and beyond. Factors predicting OS (P value by log rank <0·05) were: comorbidity index <3, FISH rank (Dohner) and 17p deletion, alemtuzumab pre-HSCT, achievement of CR post-HSCT, donor chimerism >90%, clearance of FISH abnormality post-HSCT and absence of high-grade (3-4) graft-versus-host disease. Results from this province-wide, two-decade cohort demonstrated that a substantial proportion of patients with high-risk CLL become long term disease-free survivors.